Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims

ABSTRACT

The invention involves a method for treating a human survivor of a heart attack and provides further improvement in survival following the heart attack by the early initiation and long-term administration of an angiotensin converting enzyme inhibitor. The angiotensin converting enzyme inhibitor may be used on its own, or in conjunction with other therapeutic compounds such as data blockers and thrombolytic agents. The preferred angiotensin converting enzyme inhibitor is captopril.

Survivors of acute myocardial infarction are at greatly increased riskfor subsequent fatal and non-fatal cardiovascular events (1). Thisheightened risk is not a uniform one, but rather is influenced by manyfactors such as age, co-morbid diseases, extent of coronary arterydisease, electrical stability, and, most importantly, the severity ofleft ventricular dysfunction. Irrespective of how the latter is measured(ventricular volumes, ejection fraction, contraction score), theseverity of dysfunction correlates highly with mortality and thus isuseful in stratifying survivors of acute myocardial infarction intocategories of varying risk (2,3,4,5). Of these indices of leftventricular impairment, the most powerful predictor of survival isventricular volume (4,5).

In a rat model of myocardial infarction produced by ligation of the leftcoronary artery, progressive left ventricular dilation has been shown tooccur as a function of the size and age of the infarct (6,7). During theacute post-infarction phase, prior to scar formation, an increase inventricular diastolic volume occurs as a consequence of infarctexpansion and a rise in filling pressure (8,9). Following formation of adiscrete scar, left ventricular dilation may continue as the result of aremodeling of the residual viable myocardium, initially acting torestore stroke volume (9, 10). If the infarct is of sufficient size, theincrease in diastolic volume may progress, leading to furtherdeterioration in ventricular performance and perpetuation of thedilatation (11). In a rat model of myocardial infarction, the chronicadministration of the angiotensin converting enzyme inhibitor,captopril, has been shown to attenuate this gradual dilatation of theleft ventricle both by remodeling its structure and reducing itsdistending pressure, leading to an improvement in cardiac function (12)and, in long-term studies, a prolongation of survival (12,13).

Although this animal data is encouraging, it is by no means predictiveof what will happen in humans. In fact, the NIH has been critical ofpre-clinical data based upon rat models (personal communication), and arecent clinical trial based upon rat data of improved survival withtherapy (milirone) resulted in an opposite conclusion (excess death) inhumans (14).

Recently, several clinical studies have confirmed the progressive natureof left ventricular enlargement and dysfunction in patients during thelate phase following a myocardial infarction (10,15). So too has chronictherapy with angiotensin converting enzyme inhibition been shown toattenuate ventricular enlargement and prevent a further deterioration ofperformance in this patient population (16, 17). Although the endpointsin these studies, e.g., ventricular size and function, werewell-defined, the sample sizes were too small to address the criticalclinical issue, i.e., the influence of angiotensin converting enzymeinhibitor therapy on long-term survival and clinical outcome.

One recent study, initiated after ours, set out to test whethertreatment for six months with an angiotensin converting enzyme inhibitor(enalapril) might have a beneficial effect on mortality in patients whohave had myocardial infarction. That study concluded that there was nobeneficial effect on mortality. In fact, the study was terminated"because of a recommendation of the safety committee" (18).

It is an object of the invention to provide a method for increasing thechances of survival in humans who have had a heart attack.

Another object of the invention is to provide a method for lesseningdeterioration in cardiac performance and improving clinical outcome inhuman survivors of a heart attack.

SUMMARY OF THE INVENTION

The invention involves treating a human survivor of a heart attack byadministering a therapeutically effective amount of an angiotensinconverting enzyme inhibitor. This treatment is intended for patients whoare otherwise free of indications for angiotensin converting enzymeinhibitor. The invention reduces the chances of adverse healthconsequences that occur following a heart attack.

Preferably, the administration of the angiotensin converting enzymeinhibitor is early and long-term. It is desirable, however, to begin thetreatment only after three days have elapsed from the date of the heartattack, and it further is desirable to gradually increase the dose. Mostpreferably, the angiotensin converting enzyme inhibitor is captopril.

The angiotensin converting enzyme inhibitor may be used alone or inconjunction with other compounds that are known to reduce adverse healthconsequences that occur following a heart attack. For example, thebeneficial results of treatment with captopril are present whencaptopril is administered in conjunction with either beta-adrenergicblocking agents or thrombolytic agents.

These and other aspects of the invention will be described in greaterdetail below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting all cause mortality for placebo treatedsurvivors compared to captopril treated survivors.

FIG. 2 is a bar graph depicting adverse health consequences for placebotreated survivors compared to captopril treated survivors.

FIG. 3 is a graph depicting cardiovascular mortality for placebo treatedsurvivors compared to captopril treated survivors.

FIG. 4 is a graph depicting congestive heart failure (requiringangiotensin converting enzyme inhibition treatment) for placebo treatedsurvivors compared to captopril treated survivors.

FIG. 5 is a graph depicting congestive heart failure (requiringhospitalization) for placebo treated survivors compared to captopriltreated survivors.

FIG. 6 is a graph depicting recurrent myocardial infarction for placebotreated survivors compared to captopril treated survivors.

FIG. 7 is a graph depicting cardiovascular mortality plus recurrentmyocardial infarction for placebo treated survivors compared tocaptopril treated survivors.

FIG. 8 is a graph depicting cardiovascular mortality plus morbidity forplacebo treated survivors compared to captopril treated survivors.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a treatment for heart attack survivors.It involves therapy with an angiotensin converting enzyme inhibitor insurvivors with depressed left ventricular ejection fraction but withoutovert heart failure, and it results in reductions in total andcardiovascular mortality, in the frequency of development of severecongestive heart failure (treatment failure) and of recurrent myocardialinfarction, and in the proportion of patients who either died orsurvived with a marked deterioration in left ventricular ejectionfraction.

Angiotensin converting enzyme (ACE) inhibitors are known to be useful asantihypertensive agents and for treating congestive heart failure. Theaction of the enzyme renin on angiotensin, a pseudoglobulin in bloodplasma, produces angiotensin I. Angiotensin I is converted byangiotensin converting enzyme (ACE) to angiotensin II. The latter is anactive pressor substance which has been implicated as the causativeagent in several forms of hypertension in various mammalian species,e.g., humans. ACE inhibitors intervene in theangiotensin→(renin)→angiotensin I→angiotensin II sequence by inhibitingangiotensin converting enzyme and reducing or eliminating the formationof the pressor substance angiotensin II.

Classes of compounds known to be useful as ACE inhibitors includeacylmercapto and mercaptoalkanoyl prolines such as captopril (Ondetti etal. U.S. Pat. No. 4,105,776) and zofenopril (Ondetti et al. U.S. Pat.No. 4,316,906), carboxyalkyl dipeptides such as enalapril (Harris et al.U.S. Pat. No. 4,374,829), lisinopril (Id.), quinapril (Hoefle et al.U.S. Pat. No. 4,344,949), ramipril (Gold et al. U.S. Pat. No.4,587,258), and perindopril (Vincent et al. U.S. Pat. No. 4,508,729),carboxyalkyl dipeptide mimics such as cilazapril (Attwood et al. U.S.Pat. No. 4,512,924) and benazepril (Watthey, U.S. Pat. No. 4,410,520),and phosphinylalkanoyl prolines such as fosinopril (Petrillo, U.S. Pat.No. 4,337,201).

The foregoing compounds never before have been given early and forextended periods of time to heart attack survivors who are otherwisefree of indications for ACE inhibitors. By "free of indications for ACEinhibitors", it is meant that the survivor does not have symptoms or aclinical history that call for treatment with an ACE inhibitor (otherthan the indication which exists as a result of this invention). Inother words, treatment is given to survivors who do not exhibit, amongother things, symptomatic congestive heart failure or systemichypertension. By "long-term" or "extended period" it is meant greaterthan six months. Preferably, the ACE inhibitor is administeredcontinuously and substantially without interruption for at least twoyears.

In the preferred embodiment, the ACE inhibitor is not administered tothe survivor immediately following the heart attack. Instead, the startof medication is delayed for several days, preferably three. Inaddition, it is preferred that the survivor first receive a relativelylow dose of the ACE inhibitor, gradually increasing that dose to themaximum tolerable dose. By "maximum" dose, it is meant the highest dosethat is free of medically unacceptable side effects, i.e., the highestsafe dose according to sound medical judgment. By "tolerable" dose, itis meant the highest dose that a patient is willing to take. It thuswill be understood by those of ordinary skill in the art that althoughthe maximum dose may be preferred, any particular survivor may insist ona lower dose for medical reasons, for psychological reasons or forvirtually any other reason.

In the most preferred embodiment, the ACE inhibitor is a tabletcontaining captopril (U.S. Pat. No. 4,105,776, sold by Bristol-MyersSquibb). The captopril is administered orally in tablet form, beginningthree days after the heart attack (and preferably not later than sixteendays after the heart attack). It is administered first at a dose of lessthan 20 mg per day, and gradually increased to the maximum dose of 150mg per day. Preferably the captopril is administered three times per dayto achieve these doses.

Somewhat surprisingly, the ACE inhibitor still achieves a beneficialeffect when co-administered with non-ACE inhibitor compounds that reducethe risk of adverse health consequences occurring after a heart attack.For example, aspirin, beta-adrenergic blocking agents, anticoagulantsand thrombolytic agents are known to produce beneficial effects whenadministered to heart attack survivors. When the ACE inhibitors areco-administered with such compounds, the effect is cumulative; that is,the beneficial effects of the invention are present over and above thebeneficial effects of the other compounds.

The ACE inhibitor may be administered by any medically-acceptable route,including oral, rectal, topical, nasal, transcutaneous or parenteral(e.g., subcutaneous, intermuscular and intravenous) routes. Thepreferred route is oral. Formulations of the ACE inhibitor suitable fororal administration include discrete units such as capsules, tablets,lozenges and the like. The preferred formulation is a tablet.

The ACE inhibitors are administered in therapeutically effectiveamounts. By "therapeutically effective amount", it is meant that amountnecessary to achieve a reduction in the risk of adverse healthconsequences. Adverse health consequences include congestive heartfailure, recurrent myocardial infarction and/or death. The effectiveamount will vary according to the particular ACE inhibitor used and themode of administration. It also may vary according to individual patientparameters including age, physical condition, size and weight. Thesefactors are well-known to those of ordinary skill in the art and can besuitably addressed with no more than routine experimentation.

As will be demonstrated in the example to follow, the early initiationand continued administration of an ACE inhibitor, captopril, to patientswith asymptomatic left ventricular dysfunction following an acutemyocardial infarction improved long-term overall survival and reducedthe mortality and morbidity due to major cardiovascular events. Inparticular, overall deaths were reduced; congestive heart failurerequiring ACE inhibitor treatment was reduced; and congestive heartfailure requiring hospitalization was reduced. Additionally, of thepatients who developed congestive heart failure, survival was improvedfor those who had been receiving the ACE inhibitor prior to developingthe symptoms of congestive heart failure.

EXAMPLE

Study Organization

The trial was a randomized, double-blind, placebo-controlled trial of2231 patients with an acute myocardial infarction and left ventriculardysfunction who were enrolled at 45 clinical centers.

Patient Recruitment

The enrollment phase of the trial began on Jan. 27, 1987 and ended onJan. 28, 1990. To be considered for recruitment, patients of eithergender had to survive the first three days of a myocardial infarctionwith a radionuclide left ventricular ejection fraction≦40 percent and beat least 21 but under 80 years of age. A myocardial infarction wasconsidered to have occurred if the patient experienced either (1) acutechanges in an electrocardiogram (Q or QS finding plus ST elevationand/or T-Wave inversion plus absence of left bundle branch block orWolff-Parkinson-White syndrome) obtained shortly after the infarctionwith the attendant clinical symptoms and elevation in myocardial enzymesor (2) the presence of changes in Q-waves on serial electrocardiogramsdemonstrated a myocardial infarction had occurred or (3) the patient hadan elevation of myocardial enzymes that were twice as high as normallevels and typical symptoms of a myocardial infarction were present.

Exclusions to enrollment included: women of child bearing potentialunless contraception was used; patients with malignancy thought toreduce survival or requiring radiation therapy; severe valvular heartdisease likely to require a surgical procedure; psychologic disordermaking the patient unsuitable for a clinical trial; participation inanother investigational drug trial; clinical ischemia with no correctiveprocedure prior to the scheduled time of randomization; ischemia orsymptomatic hypotension following the test dose of captopril; failure torandomize within 16 days of the myocardial infarction; relativecontraindication to the use of an angiotensin converting enzymeinhibitor or its requirement for the management of symptomaticcongestive heart failure or systemic hypertension; a serum creatininelevel>221 μmol/liter (2.5 mg/dl); other conditions thought to limitsurvival; an unwillingness or inability to participate in a long-termtrial; and an unstable course following infarction.

The presence of recurrent ischemic discomfort 72 hours after the onsetof the index myocardial infarction, a positive exercise test (≧2 mm STsegment depression and failure to complete the modified exerciseprotocol), required that cardiac catheterization and coronaryarteriography be performed and a clinical decision made regarding theneed for myocardial revascularization. If required, revascularizationhad to be performed so as to allow patients to be randomized three to 16days post-infarction. Of the 8938 patients considered eligible by thisinitial screening process, 2250 (25.2 percent) had no exclusions andconsented to participate in the trial. Prior to randomization, alleligible and consenting patients were given a test dose of open-labelcaptopril 6.25 mg orally. If this initial dose was well tolerated andnot associated with significant orthostatic or ischemic symptoms, thepatient was randomized to receive either captopril or placebo therapy ina double-blind fashion.

The test dose of 6.25 mg (p.o.) of captopril resulted in the exclusionof 3 patients for associated ischemic discomfort and 16 patients forsymptomatic hypotension, yielding a study population of 2231. A moredetailed presentation of the screening process and the exclusions toenrollment has been published in The American Journal of Cardiology(19), the entire disclosure of which is incorporated herein byreference.

Randomization, Dose Titration, and Follow-up

Randomization to therapy with either placebo or captopril was achievedby computer-generated allocation and was stratified by center. Twoadditional stratifications, based on age (above and below 70 years) andleft ventricular ejection fraction (above and below 20 percent), insuredthat the subsets of patients (age above 70 years and/or ejectionfraction below 20 percent) who were at highest risk for adverse eventswould be evenly distributed between the two therapy groups. The initialdose of the blinded medication was 12.5 mg. However, investigators wereallowed to administer a 6.25 mg dose to those patients who had a marked,yet asymptomatic reduction in blood pressure with the test dose. Thetarget dose of study medication was 25 mg three times daily by the endof the in-hospital phase and was titered to a maximum of 50 mg threetimes daily following discharge from the hospital. If the investigatorperceived any adverse experience to the medication, a reduction in dosewas permitted. Outpatient visits were begun two weeks afterrandomization, then scheduled at intervals of three months during thefirst year of follow-up and at intervals of four months during theremainder of the trial. All patients were followed for a minimum of twoyears.

At each follow-up visit, a physical examination was performed andinterim clinical events were ascertained. Symptoms of myocardialischemica were noted as was the development of signs and symptoms ofcongestive heart failure. Patients were categorized according to thepresence of severe congestive heart failure at any time during thefollow-up period. Assessed, in addition, were the occurrence ofrecurrent myocardial infarction as well as possible adverse effects ofstudy medication. During the last ten months of follow-up, all survivingpatients were to have a repeat radionuclide ventriculogram. The protocolcall for temporary (48 hours) suspension of the study medication priorto repeat determination of the ejection fraction; study medication thenwas resumed and continued for the remainder of the trial. On average,this repeat ejection fraction was obtained 36 months (range, 15 to 57months) following randomization.

End Points

Observation was continued to the planned completion date of Jan. 31,1992, by which time the last patient enrolled had finished a minimumfollow-up period of two years. Several prospectively defined measures ofoutcome served as end points in the trial: all cause mortality¹ ;cardiovascular mortality; mortality combined with a fall in ejectionfraction of at least 9 units in survivors; cardiovascular morbidity,defined as the development of severe congestive heart failure or therecurrence of a fatal or non-fatal myocardial infarction; and thecombination of cardiovascular mortality and morbidity. Two endpoints ofsevere heart failure (treatment failure) were prospectively defined: 1)patients who developed and remained in overt heart failure despite theadministration of diuretics and digitalis and who therefore requiredangiotensin converting enzyme inhibition therapy. After determining thatthe patient could not be managed adequately by conventional therapy(diet, diuretics and/or digitalis), the study medication (placebo orcaptopril) was discontinued in order to initiate therapy with open-labelangiotensin converting enzyme inhibitor (for the already approved usefor symptomatic heart failure); and, 2) failure of outpatient treatmentand consequent hospitalization for the management of congestive heartfailure.

The change in radionuclide ventricular ejection fraction was selected asan objective measure that was anticipated to occur infrequently, butwhen present was deemed to be of major clinical significance. It wasdetermined that a change of 9 percentage points would signify a decreasethat was unlikely to be due to chance alone. In addition, observationsof repeat radionuclide ventricular ejection fraction determinationsconfirmed that patients with ejection fraction deteriorations greaterthan or equal to 9% were experiencing an increased risk of death, makingthis magnitude of deterioration clinically relevant.

Statistical Analysis

The statistical method has been described in detail previously (19). Asample size of 2200 patients was estimated. All analyses were asintention to treat and all P values were two-sided. Comparability ofbase-line characteristics of the two treatment groups was ascertained bychi-square tests for categorical variables and standard normal (z) testsfor continuous variables. A proportional hazards regression model withtime-dependent covariates was used to assess the relative risk of deathfor patients who experienced heart failure requiring therapy withopen-label angiotensin converting enzyme inhibitor or hospitalization. Achi-square test statistic for comparing the occurrence of endpointsacross a treatment group was performed and its results are displayed inthe text and tables. The analysis of the combined endpoint of theoccurrence of either death or survival and a≧9 unit reduction inejection fraction, which considered the time to death or a change of ≧9units of ejection fraction in survivors, was based on the Gehanstatistic (20). Kaplan-Meier estimates were used to assess thedifferences in the distributions of time from randomization to theclinical event of interest as displayed in the life table figures (1 and3). The log-rank test statistic was used to analyze the life-table dateby therapy assignment for the first four years of follow-up.

Results

The 2231 patients enrolled in the trial were followed for an average of43±10 months, from the prospectively defined minimum of 24 months to amaximum of 60 months. At the completion of this follow-up period, thevital status of 6 patients (3 placebo and 3 captopril) had not yet beenascertained. There were no differences in the characteristics of thepatients assigned to placebo or of captopril at the time just prior torandomization. Blood pressure increased in both treatment groups frombase line to three months, albeit to differing extents, so that bothsystolic and diastolic pressures of the placebo group were significantlyhigher than those in the captopril group at three months. Thisdifference was maintained during follow-up (one-year visit for placebo,125±18/77±10 and for captopril, 119±18/74±10 mmHg; P<0.001, for bothsystolic and diastolic pressures). The heart rate for both groups was,on average, 72 beats per minute.

Mortality

From the onset (Jan. 27, 1987) to the termination (Jan. 31, 1992) of thetrial, there were 502 deaths, of which 274 of 1116 (24.6 percent) werein the placebo group and 228 of 1115 (20.4 percent) in the captoprilgroup; the reduction in risk for all cause mortality was 17 percent (95percent confidence interval, 3 to 29 percent; P=0.020) (FIG. 1, Table1).

A repeat ejection fraction was obtained in 1642 of the 1729 survivingpatients [95 percent (805/842) of those on placebo and 94 percent(837/887) of those on captopril] and a deterioration of 9 or more unitswas noted in 15 percent (124/805) of the patients in the placebo groupand in 13 percent (110/835) of the patients in the captopril group(P=0.190). When this measure of progressive left ventricular dysfunctionwas combined with all cause mortality, this prospectively definedendpoint was realized in 36 percent (398/1116) of patients on placeboand in 30 percent (338/1115) of patients on captopril; the reduction inrisk was 15 percent (95 percent confidence interval, 4 to 25 percent;P=0.007) (Table 1).

                  TABLE 1                                                         ______________________________________                                        Total Mortality and Survival With Deterioration in Left Ventricular            Ejection Fraction According to Treatment Group.                                                              RISK                                                                                     PLACEBO CAPTOPRIL REDUCTION                                                   (N = 1116) (N = 1115) (95% CI)     EVENT    (number percent) percent    P Value                                  ______________________________________                                        All Cause                                                                              274 (24.6)                                                                              228 (20.4) 17 (3 to 29)                                                                           0.020                                    Mortality                                                                     Alive and 124 (11.1) 110 (9.9) 11 (-13 to 30) 0.303                           Observed                                                                      Reduction                                                                     LVEF ≧ 9                                                               units                                                                         Death or 398 (35.7) 338 (30.3) 15 (4 to 25) 0.007                             Reduction                                                                     LVEF ≧ 9                                                               units                                                                       ______________________________________                                         Death or survival with an observed reduction in left ventricular ejection     fraction (LVEF) of ≧ 9 units was also compared with a modified         Gehan (18) statistic which considers duration between ejection fraction       determinations as well as duration of survival. This analysis also            demonstrated a significant improvement in this endpoint for patients          randomized to captopril (p = 0.020).                                     

Of the total mortality, 84 percent (421/502) of the deaths weresecondary to cardiovascular events, 233 in the placebo group and 188 inthe captopril group; the reduction in risk was 19 percent (95 percentconfidence interval, 4 to 32 percent; P=0.015) (Table 2). Within thiscategory of cardiovascular death there was a marked reduction inmortality due to cardiac pump failure in the captopril group whencompared with the placebo group (58 deaths in the placebo group versus38 in the captopril group; these 96 deaths included the twelve patientswho underwent cardiac transplantation, 7 in the placebo group and 5 inthe captopril group); the reduction in risk from cardiac pump failurewas 34 percent (95 percent confidence interval, 2 to 56 percent;P=0.040). Non-cardiovascular causes accounted for 16 percent of totalmortality and were distributed evenly between the two treatment groups(Table 2). Specifically, there were no differences between the placeboand captopril groups in deaths due to neoplasm, includinggastrointestinal neoplasm.

                  TABLE 2                                                         ______________________________________                                        Causes of Death.                                                                                              RISK                                               REDUCTION                                                                  CAUSES PLACEBO CAPTOPRIL (95% CI) P                                         OF DEATH number           percent    VALUE                                    ______________________________________                                        Cardiovascular                                                                         233       188        19 (4 to 32)                                                                           0.015                                    Atherosclerotic 221 174 21 (6 to 34) 0.009                                    Heart Disease                                                                 Pump failure 58 38 34 (2 to 56) 0.040                                         Sudden with 50 43  NS                                                         preceding                                                                     symptoms                                                                      Sudden 75 62  NS                                                              unexpected                                                                    Acute MI 24 24  NS                                                            Cardiac 9 5  NS                                                               Procedure                                                                     Other cardiac 5 2  NS                                                         Vascular 12 14  NS                                                            Non-Cardio- 41 40  NS                                                         vascular                                                                      Cancer 20 14  NS                                                              Infection/ 18 16  NS                                                          Gastrointestinal                                                              Bleed                                                                         Traumatic/ 3 10  NS                                                           Unknown                                                                       TOTAL 274 228 17 (3 to 29) 0.020                                            ______________________________________                                    

Cardiovascular Morbidity

FIG. 2 is a bar graph depicting cardiovascular morbidity and mortalityin the captopril and placebo groups. The total bar represents the numberof patients experiencing the event in each group and the symboldesignates a significant reduction in the event for captopril-treatedpatients. The lower solid portion of each bar represents the number ofpatients who manifested the specific cardiovascular event andsubsequently died; the symbol next to the solid bar designates asignificant reduction in the mortality of the captopril-treated patientsexperiencing the event (*P<0.05;+P<0.005).

The incidence of failure of treatment of congestive heart failure withdigitalis and diuretics requiring open-label therapy with angiotensinconverting enzyme inhibitor increased progressively during the average43 months of follow-up: 13 percent (295/2231) of the enrolled populationmanifested this degree of heart failure (FIG. 2). Irrespective oftherapy assignment, this need for the use of open-label angiotensinconverting enzyme inhibitor was associated with an increased risk ofdeath: 37 percent (110/295) of those patients who exhibited this degreeof heart failure went on to die, while 20 percent (392/1936) of thosepatients who did not require an angiotensin converting enzyme inhibitordied during the period of observation (relative risk=2.3; 95 percentconfidence interval, 2.0 to 3.1; P<0.001). However, patients randomizedto receive captopril were significantly less likely to exhibit this formof treatment failure when compared with those on placebo [179 of 1116(16.0 percent) on placebo versus 116 of 1115 (10.4 percent) oncaptopril]; the reduction in risk for requiring open-label angiotensinconverting enzyme inhibition was 36 percent (95 percent confidenceinterval, 19 to 48 percent; P<0.001) (FIG. 2). The group randomized tocaptopril also exhibited a considerable reduction in the number ofpatients who died subsequent to going on open-label therapy with anangiotensin converting enzyme inhibitor (71 on placebo versus 39 oncaptopril; the reduction in risk was 45 percent; 95 percent confidenceinterval, 19 to 62 percent; P=0.002) (FIG. 2).

Treatment failure resulting in the need for hospitalization for themanagement of congestive heart failure was an even worse prognosticsign: 15 percent (345/2231) of the enrolled population manifested thisdegree of heart failure. Irrespective of therapy assignment, therequirement of hospitalization for the management of congestive heartfailure was associated with a markedly increased risk of death: 48percent (165/345) of those patients who exhibited this degree of heartfailure went on to die while 18 percent (337/1886) of those patients whowere not hospitalized for heart failure died (relative risk=3.3; 95percent confidence interval, 2.5 to 4.0; P<0.001). Randomization tocaptopril therapy reduced the number of patients who requiredhospitalization for congestive heart failure (placebo: 17 percent, 191of 1116 versus captopril: 14 percent, 154 of 1115; the reduction in riskfor hospitalization for heart failure was 19 percent; 95 percentconfidence interval, 2 to 34 percent; P=0.031). The captopril group alsoexhibited a substantial reduction in the number of patients who werehospitalized for congestive heart failure and who subsequently died (101on placebo versus 64 on captopril; the reduction in risk was 37 percent;95 percent confidence interval, 14 to 53 percent; P=0.003) (FIG. 2).

There were 301 confirmed, recurrent myocardial infarctions, 167 of whichoccurred in the placebo group and 134 in the captopril group; thereduction in risk was 20 percent (95 percent confidence interval, 1 to35 percent; P=0.042) (FIG. 2). The number of deaths following arecurrent myocardial infarction tended to be lower in the captoprilgroup when compared with placebo (placebo, 76 and captopril, 57); thereduction in risk was 25 percent (95 percent confidence interval, -5 to46 percent; P=0.090).

FIGS. 3-8 show life table graphs which illustrate the beneficial effectof captopril therapy in reducing the incidence of the major adversecardiovascular events. FIG. 3 shows the benefit of captopril therapy fordecreasing cardiovascular mortality; FIG. 4 shows the benefit ofcaptopril therapy for reducing the incidence of congestive heart failurerequiring ACE inhibition; FIG. 5 shows the benefit of captopril therapyfor decreasing the incidence of hospitalization due to heart failure;FIG. 6 shows the benefit of captopril therapy for reducing recurrentmyocardial infarction; FIG. 7 shows the benefit of captopril therapy forreducing both cardiovascular mortality and recurrent MI; and FIG. 8shows the benefit of captopril therapy for reducing both cardiovascularmortality and morbidity (severe heart failure requiring either ACEinhibitor therapy, hospitalization, or development of recurrentmyocardial infarction). (For all combined analyses, only the time tofirst event was utilized).

The effect on all cause mortality and cardiovascular mortality andmorbidity of major, prospectively specified, pre-randomizationcharacteristics known to influence survival following myocardialinfarction was as anticipated; that is, irrespective of treatmentassignment, advanced age, history of prior myocardial infarction, lowerleft ventricular ejection fraction, and higher Killip Classificationwere associated with a greater incidence of adverse events. When thesesubgroups were analyzed, captopril therapy showed a consistent benefit,although to varying degrees, in reducing all cause mortality andcardiovascular mortality and morbidity (Table 3). Of particular note wasthe efficacy of captopril in Killip class I patients, i.e., those whodid manifest even transient pulmonary congestion at the time of theiracute myocardial infarction. Captopril also was efficacious in patientswho were receiving beta-blocking agents at the time of randomization,illustrating its additive value to an already proven therapy for themanagement of patients following a myocardial infarction. Thedirectional benefit of captopril was uniform, for in no instance was itseffect on risk reduction discordant within subgroups.

                  TABLE 3                                                         ______________________________________                                        Effect of Captopril on Major Clinical                                           Endpoints in Various Subgroups Known to Have Important                        Influence on Survival Following Myocardial Infarction                                                          RISK                                            REDUCTION                                                                  VARIA- PLACEBO CAPTOPRIL (95% CI)                                           BLE    events/number (percent)                                                                             percent                                          ______________________________________                                        DEATH (ALL CAUSE)                                                               Age                                                                           (years):                                                                      ≦55  54/365 (14.8)  52/375 (13.9)  6 (-34 to 34)                       56-64  76/352 (21.6)  69/356 (19.5) 10 (-20 to 33)                            >64 144/399 (36.1) 107/384 (27.9) 23  (5 to 37)                               Sex:                                                                          male 233/912 (25.5) 191/929 (20.6) 20  (5 to 32)                              female  41/204 (20.1)  37/186 (19.9)  1 (-47 to 33)                           Prior MI:                                                                     No 143/721 (19.8) 115/718 (16.0) 19  (-9 to 35)                               Yes 131/395 (33.2) 113/397 (28.5) 14  (-6 to 30)                              EF                                                                            (percent):                                                                    >31  76/517 (14.7)  75/531 (14.1)  4  (-3 to 29)                              ≦31 198/599 (33.1) 153/584 (26.2) 26  (12 to 38)                       Killip                                                                        Class:                                                                        I 139/672 (20.7) 109/676 (16.1) 22  (2 to 38)                                 II or 135/444 (30.4) 119/442 (26.9) 11 (-10 to 28)                            higher                                                                        MI Clas-                                                                      sification                                                                    by ECG:                                                                       Anterior Q 117/605 (19.3) 112/624 (17.9)  7 (-17 to 27)                       Inferior Q  40/193 (20.7)  36/201 (17.9) 13 (-30 to 42)                       Both  48/135 (35.6)  30/126 (23.8) 34  (1 to 54)                              Non Q  34/110 (30.9)  22/106 (20.8) 35  (-4 to 60)                            Other 35/73 (47.9) 28/58 (48.3) -1 (-44 to 30)                                Throm-                                                                        bolytic                                                                       Therapy:                                                                      Yes  58/355 (16.3)  48/376 (12.8) 22 (-11 to 45)                              No 216/761 (28.4) 180/739 (24.4) 14  (2 to 28)                                Beta                                                                          Blocker:                                                                      Yes  76/398 (19.1)  52/391 (13.3) 30  (4 to 50)                               No 198/718 (27.6) 176/724 (24.3) 12  (-5 to 26)                               Randomi-                                                                      zation                                                                        days:                                                                         3-7  49/197 (24.9)  40/177 (22.6)  9 (-31 to 37)                              8-9  67/318 (21.1)  67/331 (20.2)  4 (-30 to 29)                              10-12  50/203 (24.7)  39/199 (19.6) 20 (-15 to 45)                            13-16 108/398 (27.1)  82/408 (20.1) 26  (5 to 42)                             TOTAL  274/1116 (24.6)  228/1115 (20.4) 17  (3 to 29)                       CV DEATH OR MORBIDITY*                                                          Age                                                                           (years):                                                                      ≦55 103/365 (28.2)  99/375 (26.4)  6 (-18 to 26)                       56-64 152/352 (43.2) 111/356 (31.2) 28  (12 to 41)                            >64 191/399 (47.9) 150/384 (39.1) 18  (4 to 31)                               Sex:                                                                          male 367/912 (40.2) 290/929 (31.2) 22  (12 to 31)                             female  79/204 (38.7)  70/185 (37.8)  3 (-25 to 25)                           Prlor MI:                                                                     No 226/721 (31.3) 185/718 (25.8) 18  (3 to 30)                                Yes 220/395 (55.7) 175/397 (44.1) 21  (9 to 31)                               EF                                                                            (percent):                                                                    >31 154/517 (29.8) 123/531 (23.2) 22  (5 to 37)                               ≦31 292/599 (48.7) 238/584 (40.8) 17  (5 to 27)                        Killip                                                                        Class:                                                                        I 224/672 (33.3) 180/676 (26.6) 20  (6 to 32)                                 II or 222/444 (50.0) 180/442 (40.7) 19  (6 to 30)                             higher                                                                        MI Clas-                                                                      sification                                                                    by ECG:                                                                       Anterior Q 197/605 (32.6) 178/624 (28.5) 12  (-4 to 26)                       Inferior Q  76/193 (39.4)  61/201 (30.3) 23  (-1 to 41)                       Both  74/135 (54.8)  50/126 (39.7) 28  (6 to 44)                              Non Q  51/110 (46.4)  38/106 (35.8) 23  (-7 to 44)                            Other 48/73 (65.8) 33/58 (56.9) 13 (-14 to 35)                                Throm-                                                                        bolytic                                                                       Therapy:                                                                      Yes 117/355 (33.0)  99/376 (26.3) 20  (0 to 36)                               No 329/761 (43.2) 261/739 (35.3) 18  (7 to 28)                                Beta                                                                          Blocker:                                                                      Yes 132/398 (33.2) 102/391 (26.1) 21  (2 to 37)                               No 314/718 (43.7) 258/724 (35.6) 19  (7 to 28)                                Randomi-                                                                      zation                                                                        days:                                                                         3-7  82/197 (41.6)  66/177 (32.3) 10 (-15 to 30)                              8-9 115/318 (36.2) 101/331 (33.3) 16  (-5 to 32)                              10-12  84/203 (41.4)  61/199 (30.8) 26  (3 to 43)                             13-16 165/398 (41.5) 132/408 (32.4) 22  (6 to 35)                             TOTAL  446/1116 (40.4)  360/1115 (33.3) 19  (10 to 28)                      ______________________________________                                         *CV Death or Morbidity designates either a death classified as having a       cardiovascular origin or the development of congestive heart failure          requiring the use of openlabel angiotensin converting enzyme inhibitor fo     management of congestive heart failure, the development of heart failure      requiring a hospital admission for management, or a recurrent myocardial      infarction. With this analysis, any patient can only experience one of        these major fatal or nonfatal  #cardiovascular events. The percentage ris     reduction and 95% confidence interval (CI) are indicated in brackets.         EF indicates radionuclide left ventricular fraction at baseline.              MI indicates myocardial infarction.                                           ECG indicates electrocardiogram.                                         

Adherence and Adverse Study Drug Experience

The number of patients taking their assigned study medication atone-year was similar for the placebo (784/989, 79 percent) and captopril(762/1000, 76 percent) groups (P=NS). At the last study visit, 73percent (614/842) of the patients in the placebo group and 70 percent(624/887) of the patients in the captopril group were still on studydrug (P=NS). Of those taking their assigned study medication at the lastvisit, 90 percent (551/614) of placebo and 78 percent (486/624) ofcaptopril patients achieved the target dose of 150 mg per day.

Captopril-treated patients registered significantly more (Z>1.96,uncorrected; excess over placebo) complaints of dizziness (5.5 percent);taste alteration (2.5 percent); diarrhea (2.1 percent); and cough (6.2percent). The number of patients who discontinued study medicationduring the first three years of follow-up because of these adverseeffects in the placebo and captopril groups, respectively, was: 26 and50 for dizziness (P=0.005); 14 and 16 for taste alteration (P=NS); 31and 51 for cough (P=0.024); and none for diarrhea. A minor, butstatistically significant difference in the serum creatinine level wasdetected between the treatment groups during the follow-up period(two-year values for placebo and captopril, respectively: 106 versus 110μmol/liter, or 1.20 versus 1.24 mg/dl; P=0.014).

DISCUSSION

The randomization window of 3 to 16 days was chosen to allow thetreating physician time to formulate an individualized plan for themanagement of coronary artery disease. Indeed, of the total studypopulation, 55 percent had a catheterization and 26 percent had arevascularization procedure (9 percent had coronary artery bypasssurgery and 17 percent had percutaneous transluminal coronaryangioplasty) performed following the infarction but prior to enrollment.Although this randomization period precluded the opportunity forcaptopril to influence the early (<72 hours) changes in left ventriculartopography that may occur following myocardial infarction (21), thelong-term efficacy of captopril therapy in reducing adverse clinicalevents did not appear to be influenced by the differences in the time toinitiation of therapy (Table 3).

The selection of patients with objective evidence of left ventriculardysfunction (ejection fraction≦40 percent) was based on the finding inprevious clinical studies (16,17) that captopril attenuated ventriculardilatation in this patient population. The exclusion from this trial ofpatients with symptomatic heart failure who required vasodilators wasbased on the demonstrated efficacy of this therapy for the treatment ofheart failure (22,23,24). In the present study the efficacy of captopriltherapy in reducing death and major adverse cardiovascular eventsappeared to increase during follow-up (FIGS. 1 and 3-8), underscoringthe value of this agent as preventive therapy in patients with leftventricular dysfunction but without overt heart failure following amyocardial infarction. The present study demonstrates that the long-termadministration of captopril to survivors of a myocardial infarction, ahigh risk population, resulted in a reduction not only in themanifestation of heart failure, but also in the number of subsequentfatal events.

Although not wishing to be bound by any particular theory, the favorableeffects of captopril therapy may be explained by its attenuation ofventricular remodeling and/or by its direct inhibition of the proposeddeleterious effects of neurohumoral activation (25). These purportedmechanisms by which captopril might exert its beneficial effects are notmutually exclusive. Indeed, the combination of ventricular enlargementand elevated plasma levels of neurohormones at base line was associatedwith a greater risk of death than that for the presence of these adverseprognostic indicators alone (26). These same actions of captopril onventricular remodeling and neurohumoral profile may also be operative inreducing the incidence of recurrent myocardial infarction.

The foregoing description of the invention and the example demonstratingthe application of the invention are but illustrative. Other variationsand equivalents will be apparent to those of ordinary skill in the art.Therefore, the present invention is to be considered limited only by theappended claims.

REFERENCES

1. Kannel W B, Sorlie P, McNamara P M. Prognosis after initialmyocardial infarction: The Framingham Study. Am J Cardiol 1979; 44:53-9.

2. The Multicenter Postinfarction Research Group. Risk stratificationand survival after myocardial infarction. N Engl J Med 1983; 309:331-6.

3. Stadius M L, Davis K, Maynard C, Ritchie J L, Kennedy J W. Riskstratification for 1 year survival based on characteristics identifiedin the early hours of acute myocardial infarction. The WesternWashington Intracoronary Streptokinase Trial. Circulation 1986;74:703-11.

4. Hammermeister K E, DeRouen T A, Dodge H T. Variables predictive ofsurvival in patients with coronary disease: selection by univariate andmultivariate analyses from the clinical, electrocardiographic, exercise,arteriographic, and quantitative angiographic evaluations. Circulation1979; 59:421-30.

5. White H D, Norris R M, Brown M A, Brandt P W T, Whitlock R M L, WildC J. Left ventricular end-systolic volume as the major determinant ofsurvival after recover from myocardial infarction. Circulation 1987;76:44-51.

6. Fletcher P J, Pfeffer J M, Pfeffer M A, Braunwald E. Left ventriculardiastolic pressure-volume relations in rats with healed myocardialinfarction: effects on systolic function. Circ Res 1981; 49:618-26.

7. Pfeffer J M, Pfeffer M A, Fletcher P J, Braunwald E. Progressiveventricular remodeling in rat with myocardial infarction. Am J Physiol1991; 260 (HCP 29):H1406-14.

8. Eaton L W, Weiss J L, Bulkley B H, Garrison J B, Weisfeldt M L.Regional cardiac dilatation after acute myocardial infarction:recognition by two-dimensional echocardiography. N Engl J Med 1979;300:57-62.

9. McKay R G, Pfeffer M A, Pasternak R C, et al. Left ventricularremodeling after myocardial infarction: a corollary to infarctexpansion. Circulation 1986; 74:693-702.

10. Gaudron P, Eilles C, Ertl G, Kochsiek K. Early remodeling of theleft ventricle in patients with myocardial infarction. Europ Heart J1990; 11 (Suppl B):139-46.

11. Pfeffer M A, Braunwald E. Ventricular remodeling after myocardialinfarction. Circulation 1990; 81:1161-72.

12. Pfeffer J M, Pfeffer M A, Braunwald E. Influence of chroniccaptopril therapy on the infarcted left ventricle of the rat. Circ Res1985; 57:84-95.

13. Pfeffer M A, Pfeffer J M, Steinberg C, Finn P. Survival after anexperimental myocardial infarction: beneficial effects of long-termtherapy with captopril. Circulation 1985; 72:406-12.

14. Packer M, et al. Effect of oral milrinone on mortality in severchronic heart failure. N Engl J Med 1991; 325:1468-1475.

15. Jeremy R W, Allman K C, Bautovitch G, Harris P J. Patterns of leftventricular dilation during the six months after myocardial infarction.J Am Coll Cardiol 1989; 13:304-10.

16. Pfeffer M A, Lamas G A, Vaughan D E, Parisi A F, Braunwald E. Effectof captopril on progressive ventricular dilation after anteriormyocardial infarction. N Engl J Med 1988; 319:80-6.

17. Sharpe N, Smith H, Murphy J, Hannan S. Treatment of patients withsymptomless left ventricular dysfunction after myocardial infarction.Lancet 1988; 1:255-9.

18. Swedberg K. Lack of beneficial effects on mortality by earlyintervention with enalapril in acute myocardial infarction. Circulation1991; supplement II; 84, II-366.

19. Moye L A, Pfeffer M A, Braunwald E, for the SAVE Investigators.Rationale, design and baseline characteristics of the survival andventricular enlargement trial. Am J Cardiol 1991; 68:70D-79D.

20. Moye L A, Davis B R, Hawkins C M. Analysis of a clinical trialinvolving a combined mortality and adherence dependent interval censoredendpoint. Statistics in Medicine. January 1992. (Accepted)

21. Nabel E G, Topol E J, Galeana A, et al. A randomizedplacebo-controlled trial of combined early intravenous captopril andrecombinant tissue-type plasminogen activator therapy in acutemyocardial infarction. J Am Coll Cardiol 1991; 17:467-73.

22. Consensus Trial Study Group. Effects of enalapril on mortality insevere congestive heart failure. Results of the Cooperative NorthScandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35.

23. Cohn J N, Archibald D G, Ziesche S, et al. Effect of vasodilatortherapy on mortality in chronic congestive heart failure. Results of aVeterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.

24. The SOLVD Investigators. Effect of enalapril on survival in patientswith reduced left ventricular ejection fractions and congestive heartfailure. N Engl J Med 1991; 325:293-302.

25. Packer M, Lee W H, Kessler P D, Gottlieb S S, Bernstein J L, Kukin ML. Role of neurohormonal mechanisms in determining survival in patientswith severe chronic heart failure. Circulation 1987; 75 (SupplIV):IV-80-IV-92.

26. Sussex B A, Arnold J M O, Parker J O, et al. Independent andinteractive prognostic information of neurohormones and echocardiogramin high risk post-MI patients. J. Am. Coll. Cardiol. 1992; 19:205A(Abstract).

What we claim is:
 1. A method for treating a human survivor of amyocardial infarction who is free of hypertension and congestive heartfailure and is otherwise free of indications for angiotensin-convertingenzyme inhibition treatment to prevent repeat myocardial infarction andto increase the likelihood of survival following the myocardialinfarction, comprising:administering to the human survivor who is freeof hypertension and congestive heart failure and is otherwise free ofindications for angiotensin converting enzyme inhibition treatment atherapeutically-effective amount of an angiotensin-converting enzymeinhibitor wherein the human survivor has a left ventricular ejectionfraction of less than or equal to 40% after the myocardial infarction.2. A method for treating a human survivor of a myocardial infarction asclaimed in claim 1 wherein the angiotensin converting enzyme inhibitoris administered for an extended period of time.
 3. A method for treatinga human survivor of a myocardial infarction as claimed in claim 1wherein the angiotensin converting enzyme inhibitor is administered tothe human survivor within 16 days of myocardial infarction.
 4. A methodfor treating a human survivor of a myocardial infarction as claimed inclaim 1 wherein the angiotensin converting enzyme inhibitor isadministered to the human survivor only after 3 days have passed sincethe myocardial infarction.
 5. A method for treating a human survivor ofa myocardial infarction as claimed in claim 1 wherein the angiotensinconverting enzyme inhibitor is administered to the human survivor within16 days of the myocardial infarction, but only after three days havepassed since the myocardial infarction, and wherein the angiotensinconverting enzyme inhibitor is administered for an extended period tothe survivor.
 6. A method for treating a human survivor of a myocardialinfarction as claimed in claim 1 wherein the angiotensin convertingenzyme inhibitor is administered at a lower dose at the start oftreatment and at a higher dose after the start of treatment.
 7. A methodfor treating a human survivor of a myocardial infarction as claimed inclaim 6 wherein the higher dose is the maximum dose tolerable.
 8. Amethod for treating a human survivor of a myocardial infarction asclaimed in claim 1 wherein the angiotensin converting enzyme inhibitoris administered three times per day.
 9. A method for treating a humansurvivor of a myocardial infarction as claimed in claim 1 wherein theangiotensin converting enzyme inhibitor is administered for at least twoyears.
 10. A method for treating a human survivor of a myocardialinfarction as claimed in claim 1 wherein the angiotensin convertingenzyme inhibitor is captopril and wherein the captopril is administeredat a lower dose at the start of treatment and at a higher dose after thestart of treatment and wherein the lower dose is less than 20 mg per dayand wherein the higher dose is not more than about 150 mg per day.
 11. Amethod for treating a human survivor of a myocardial infarction asclaimed in claim 1 wherein the angiotensin converting enzyme inhibitoris captopril and the captopril is administered to the human survivoronly after three days have passed since the myocardial infarction,wherein the captopril is administered at a lower dose at the start oftreatment and at a higher dose after the start of treatment and whereinthe captopril is administered at an initial dose of about 6.25 mg, threetimes per day, a first intermediate dose of about 12.5 mg, three timesper day, a second intermediate dose of about 25 mg, three times per day,and a final dose of a tolerable amount up to about 50 mg, three timesper day.
 12. A method for treating a human survivor of a myocardialinfarction as claimed in claim 1 wherein the angiotensin convertingenzyme inhibitor is administered at the maximum dose tolerable.
 13. Amethod for treating a human survivor of a myocardial infarction asclaimed in any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, and 12, whereinthe angiotensin converting enzyme inhibitor is captopril.